PROJECT SUMMARY/ABSTRACT: Gastroparesis is a chronic, debilitating functional disorder of the stomach characterized by a delay in gastric emptying without evidence of mechanical obstruction. Classic etiologies of gastroparesis include idiopathic, post-surgical/iatrogenic, and diabetic. The incidence of gastroparesis is rapidly increasing coinciding with the diabetes epidemic in developed countries. Initial management of gastroparesis includes dietary modifications and prokinetic and/or antiemetic medications; however, these tend to lose efficacy over time and are often associated with intolerable side effects. Surgical therapy for gastroparesis is typically pursued once maximal medical therapy is no longer efficacious and may include gastric electrical stimulation, gastric bypass or subtotal gastrectomy in most cases. Disruption of the gastric pyloric sphincter (pyloroplasty, pyloromyotomy) has recently shown promise as a stomach-preserving option that does not involve the significant anatomical rearrangement required of gastrectomy. Per-oral pyloromyotomy (POP) is a novel endoscopic surgery that has shown promising utility for the management of medically refractory gastroparesis in several small single center studies. This intervention involves the division of the gastric pylorus via an endoscopic approach, accomplishing the same functional outcome of laparoscopic or open pyloromyotomy, without the invasiveness of open or laparoscopic surgery. Prior non-comparative retrospective studies have demonstrated both improvement of gastroparesis symptoms and improved gastric emptying. To date, there have been no prospective studies evaluating the efficacy of this procedure or comparisons to a control procedure. We aim to explore the utility of POP in producing symptomatic relief of gastroparesis-related symptoms as evaluated by validated scoring systems (Objective 1) and objective gastric emptying as measured by solid-phase scintigraphic gastric emptying studies (Objective 2). The proposed research is innovative in that it would additionally control for the placebo effect by blinding patients to receiving POP versus a sham intervention. This contribution would be significant as traditional gastroparesis therapies do not adequately address the clinical need, and supports the mission of the NIDDK to assess new therapeutic options in clinical trials. POP represents a potential intervention with far greater safety profile and less morbidity compared to other surgical modalities.